It is estimated that 80% of significant hearing impairment in the U.S. results from sensorineural or so-called "nerve" deafness, that usually is due to damage to or loss of the sensory hair cells that convert sound energy into electrical activity in the inner ear. This has been considered irreversible, because the production of hair cells in the human ear ceases before birth. However, these cells are produced throughout life in cold-blooded animals; in some, millions of new hair cells are added in the ear, in others hair cells can be regenerated. Also, during the last grant cycle, it was discovered that damaged hair cells in the cochleae of birds could be replaced through a process of regenerative proliferation, that could be evoked by trauma in auditory cell populations that are mitotically quiescent in undamaged ears. This application for renewal of a project in its eighth year, proposes a series of studies that will continue to investigate the cellular processes that underlie hair cell production and regenerative replacement of hair cells lost during postembryonic life. The discovery of trauma-induce regeneration in a warm-blooded animal's cochlea has provided additional support for the central thesis, that the obstacles to regeneration of hair cells in the ears of mammals are not likely to remain insurmountable, if the control of the postembryonic production of hair cells in other ears can be understood at cellular and molecular levels. The project will use the methods of tritiated-thymidine autoradiography, immunocytochemistry, electron microscopy, laser-microbeam ablation of individual cells, time-lapse video microscopy of in vivo preparations of regenerating hair cell epithelia in the lateral line system of salamanders and in vitro preparations of sensory epithelia from the frog sacculus, the chicken cochlea, and the developing organ of Corti of rodents. The objectives are: 1) definitive identification of the progenitor cells that give rise to replacement hair cells during regeneration, 2) evaluation of the potential role of hypothesized triggers that may initiate the process of regeneration, and 3) the determination of the conditions that are necessary for regeneration of hair cells to run to completion. The information sought is essential to understanding the capacities of regeneration and self-repair in hair cell epithelia. This directly pertains to possible recovery from sensorineural hearing loss and balance disorders, and to an understanding of the development of normal and abnormal function in human ears.